New materials and methods of synthesis are emerging as significant areas of research and manufacturing. They have applications in the fields of biotechnology, medicine, pharmaceuticals, medical devices, sensors, optical materials, etc. The ring-opening metathesis polymerization (ROMP) method has emerged as a powerful synthetic method for the creation of such useful materials. Many examples in which ROMP has been used to generate functionalized materials have focused on the incorporation of pendant functionality into the monomers, thereby forming a multivalent array. As used herein, a multivalent array refers to a polymer (random or blocks of varying lengths, including shorter oligomers) having pendant functional groups that impart various properties to the polymer. Such multivalent arrays are also often referred to as multivalent ligands, multivalent displays, multidentate arrays, multidentate ligands, or multidentate displays.
Such multivalent arrays are particularly useful in the medical and biotechnology areas. For example, the binding of cell surface receptors to particular epitopes of multivalent arrays can trigger a wide variety of biological responses. Such multivalent binding events have unique consequences that are dramatically different than those elicited by monovalent interactions. For instance, signaling through the epidermal growth factor is promoted by the binding of divalent ligands, which apparently promote dimerization of the transmembrane receptor, yet monovalent ligands also bind the receptor but produce no signal. In addition, multivalent arrays have been shown to induce the release of a cell surface protein, suggesting a new mechanism for controlling protein display. In protein-carbohydrate recognition processes, multivalent saccharide-substituted arrays can exhibit increased avidity, specificity, and unique inhibitory potencies under dynamic conditions of shear flow. Thus, the ability to synthesize defined, multivalent arrays of biologically relevant binding epitopes provides a means for exploring and manipulating physiologically significant processes.
One way in which this could be done is through the use of ROMP technology. ROMP has been used to generate defined, biologically active polymers (Gibson et al., Chem. Commun., 1095-1096 (1997); Biagini et al., Chem. Commun., 1097-1098 (1997); Biagini et al., Polymer, 39, 1007-1014 (1998); and Kiessling et al., Topics in Organometallic Chemistry, 1, 199-231 (1998)) with potent and unique activities that range from inhibiting protein-carbohydrate recognition events to promoting the proteolytic release of cell surface proteins (Mortell et al., J. Am. Chem. Soc., 118, 2297-2298 (1996); Mortell et al., J. Am. Chem. Soc., 116, 12053-12054 (1994); Kanai et al., J. Am. Chem. Soc., 119, 9931-9932 (1997)); Kingsbury et al., J. Am. Chem. Soc., 121, 791-799 (1999); Schrock et al., J. Am. Chem. Soc., 112, 3875-3886 (1990); Gordon et al., Nature, 392, 30-31 (1998); and Sanders et al., J. Biol. Chem., 274, 5271-5278 (1999). The assembly of multivalent materials by ROMP has several advantages over classical methods for generation of multivalent displays. Specifically, ROMP can be performed under living polymerization conditions, and if the rate of initiation is faster than that of propagation, varying the monomer to initiator ratio (M:I) can generate materials of defined length (Ivin, Olefin Metathesis and metathesis polymerization; Academic Press: San Diego, 1997). This approach has been successfully applied with the Grubb's ruthenium metal carbene catalyst ([(Cy).sub.3 P].sub.2 Cl.sub.2 Ru=CHPh) to generate materials with narrow polydispersities, indicating that the resulting substances are fairly homogeneous (Dias et al., J. Am. Chem. Soc., 119, 3887-3897 (1997); and Lynn et al., J. Am. Chem. Soc., 118, 784-790 (1996)). In contrast to anionic and cationic polymerization catalysts, ruthenium metal carbene initiators are tolerant of a wide range of functional groups.
An additional strategy for further modification is to incorporate selected functional groups at the termini. The attachment of additional functionality at polymer termini further expands the repertoire of uses for materials generated by ROMP. This selective end-capping has been used previously in living titanium and molybdenum-initiated ROMP reactions to synthesize materials for new applications, as demonstrated in the synthesis of surfaces bearing ROMP-derived polymers (Cannizzo et al., Macromolecules, 20, 1488-1490 (1987); Albagli et al., J. Phys. Chem., 97, 10211-10216 (1993); and Albagli et al., J. Am. Chem. Soc., 115, 7328-7334 (1993)). Unlike the titanium and molybdenum initiators, ruthenium ROMP initiators are tolerant of a wide variety of polar functional groups, allowing generation of products not accessible using other catalysts (Grubbs, J.M.S. Pure Appl Chem., A31, 1829-1833 (1994). The attachment of specific end groups to polymers generated by ruthenium carbene-catalyzed ROMP would provide access to materials amenable to further functionalization for applications such as selective immobilization of polymers to create new surfaces (Weck et al., J. Am. Chem. Soc., 121, 4088-4089 (1999)) and the development of specific ligands that report on binding events, for example. Thus, what is needed are methods and reagents for the incorporation of selected functionality into the terminii of polymers generated by ruthenium carbene-catalyzed ROMP.